title: Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway.
abstract: Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.
authors.affiliation: New York University Langone Medical Center, Cancer Institute, New York, NY, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Godefroy
authors.forename: Olivier
authors.initials: O
authors.lastname: Manches
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dréno
authors.forename: Tsivia
authors.initials: T
authors.lastname: Hochman
authors.forename: Linda
authors.initials: L
authors.lastname: Rolnitzky
authors.forename: Nathalie
authors.initials: N
authors.lastname: Labarrière
authors.forename: Yannick
authors.initials: Y
authors.lastname: Guilloux
authors.forename: Judith
authors.initials: J
authors.lastname: Goldberg
authors.forename: Francine
authors.initials: F
authors.lastname: Jotereau
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018448:Models, Immunological; D053278:OX40 Ligand / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D050990:GATA3 Transcription Factor; D018836:Inflammation Mediators; D018793:Interleukin-13; D053278:OX40 Ligand; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D020778:Matrix Metalloproteinase 2